Role of enterocyte Enpp2 and autotaxin in regulating lipopolysaccharide levels, systemic inflammation, and atherosclerosis

Purpose of review To explore the multiple roles that lysophosphatidic acid (LPA) plays in vascular disease and atherosclerosis. Recent findings A high-fat high-cholesterol diet decreases antimicrobial activity in the small intestine, which leads to increased levels of bacterial lipopolysaccharide in the mucus of the small intestine and in plasma that increase systemic inflammation, and enhance dyslipidemia and aortic atherosclerosis. Decreasing LPA production in enterocytes reduces the impact of the diet. LPA signaling inhibits glucagon-like peptide 1 secretion, promotes atherosclerosis, increases vessel permeability and infarct volume in stroke, but protects against abdominal aortic aneurysm formation and rupture. Acting through the calpain system in lymphatic endothelial cells, LPA reduces the trafficking of anti-inflammatory Treg lymphocytes, which enhances atherosclerosis. Acting through LPA receptor 1 in cardiac lymphatic endothelial cells and fibroblasts, LPA enhances hypertrophic cardiomyopathy. Summary LPA plays multiple roles in vascular disease and atherosclerosis that is cell and context dependent. In some settings LPA promotes these disease processes and in others it inhibits the disease process. Because LPA is so ubiquitous, therapeutic approaches targeting LPA must be as specific as possible for the cells and the context in which the disease process occurs.

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Evidence further linking the intestine to cardiovascular disease

Sulaiman,

Reddy,

Fogelman

2024

Current Opinion in Lipidology

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Purpose of review To review recent publications linking the intestine to cardiovascular disease. Recent findings Aromatic amino acid-derived metabolites produced by gut-bacteria were identified that increased or decreased the risk of cardiovascular events. Dietary phenylalanine was metabolized to phenylacetic acid by gut microbes, and converted into phenylacetylglutamine by the host, which increased thrombosis potential via adrenergic receptors and was associated with increased major adverse cardiovascular events. Another microbiota-associated metabolite of aromatic amino acids, indole-3-propionic acid, protected against heart failure with preserved ejection fraction. The mechanism by which dietary cholesterol is absorbed was found to involve the Nieman–Pick C1-like1 protein working together with a newly discovered protein called Aster. Levels of gut-derived bacterial lipopolysaccharide in serum that are an order of magnitude less than those seen in gram negative sepsis were shown to play a role in enhancing atherosclerosis and thrombosis. Summary Promising new therapeutic targets in the intestine for preventing or treating cardiovascular disease have been identified.

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Role of enterocyte Enpp2 and autotaxin in regulating lipopolysaccharide levels, systemic inflammation, and atherosclerosis

Cited by 5 publications

References 71 publications

Antibiotic intervention exacerbated oxidative stress and inflammatory responses in SD rats under hypobaric hypoxia exposure

Antibiotic intervention exacerbated oxidative stress and inflammatory responses in SD rats under hypobaric hypoxia exposure

The multiple roles of lysophosphatidic acid in vascular disease and atherosclerosis

Evidence further linking the intestine to cardiovascular disease

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